Summary of the research projects of the Neurochemistry Department

Neuronal plasticity in the rat striatum

The overall goal of this Project is to increase understanding of the nicotinic modulation of striatal dopamine release and the plastic mechanisms underlying nicotinic receptor-mediated neuroprotection, by identifying and exploiting new nicotinic ligands. This Project brings together a range of complementary expertise, comprising:

chemistry for the synthesis of novel ligands for nicotinic acetylcholine receptor (nAChR) subtypes (DrB.  Cassels, Santiag, Chile),

oocyte electrophysiology for evaluation of their subtype-selective activities at nAChR (Dr I.  Bermudez, Oxford, UK),

molecular modelling of ligands to determine the structural basis for their selectivity (DrM.  Ortells, collaborator, Buenos Aires),

in vitro neurochemistry to exploit the ligands to characterise the nicotinic modulation of dopamine release (Prof. S. Wonnacott, Bath, UK),

in vivo neurochemical studies to assess the neuroprotective potential of novel ligands and underlying mechanisms of neuroprotection in a lesion model relevant to Parkinson’s disease (Dr F. Dajas, Montevideo).

Neuronal nAChR are a family of ligand-gated ion channel (LGIC) receptors expressed in the central and peripheral nervous systems and responsive to the neurotransmitter acetylcholine (ACh). These receptors have attracted the interest as targets for therapeutic intervention in a number of diverse conditions, including neurodegenerative diseases, schizophrenia, epilepsy, anxiety and attention deficit disorder.

Of these conditions, the positive relationship between nAChR and Parkinson’s disease (PD) is perhaps the most robust: it stems from well corroborated epidemiological studies showing a negative correlation between tobacco smoking and the incidence of PD. Research carried out in the Neurochemistry Department of the Clemente Estable Institute has shown that an intermittent treatment schedule of nicotine significantly prevented the DA loss. 

We hypothesise that stimulation of nAChR  delays the degeneration of DAergic axons. This model, in which an intermittent nAChR agonist stimulation significantly slows the loss of DA in the striatal terminal fields  corresponds to a therapeutic window in the less aggressive progression of clinical PD, when a significant retardation of the neurodegeneration might be elicited through nicotinic cholinergic stimulation. The understanding of the dynamics of striatal plasticity, and the characterization and exploitation of novel nAChR agonists able to modulate striatal function is the ultimate aim of this research.

Neuroprotective South American medicinal plants

With the prolongation of the life span due to advancement of technology, brain pathology is increasingly gaining importance all over the world. Together, degenerative diseases of the nervous system affect more than 10% of the population over 65 years. Given this high prevalence, the search for new therapeutics is a scientific activity with great economic and social potential.. Nature is a rich source of new molecules and a great number of therapeutics now in use has their roots in natural products.  The flora and fauna of South America is one of the greatest in the world in the number of species, representing a still poorly explored richness.  Biodiversity is thus the most important natural resource available for South American countries, a resource whose potential for sustainable development is a challenge to be addressed at the national and international level.

The research strategy of the Neurochemistry Division aims at exploring the plant biodiversity of South America for activities in the central nervous system, mainly the potential for treating diseases like Parkinson Disease and Alzheimer´s Dementia. Since oxidative stress with its concomitant overproduction of free radicals is involved in the etiology of neurodegenerative diseases, natural compounds can be a source of lead molecules for antioxidant activity.

Results already obtained  have shown that :

a)  Achyrocline satureioides (Lam.) DC. (Asteraceae), (AS) has potent antioxidant capacity and a marked cyto and neuroprotective activity for cells in culture.

b) Haplopappus multifolius, (HM) a Chilean plant sharing flavonoid composition with AS  has also shown strong antioxidant and cytoprotective activity for cells in culture.

Accordingly with these findings, it has been hypothesized that flavonoid aglycones of a particular group, structurally related to quercetin, likely acting synergistically with other plant compounds, are responsible for the cytoprotective activity of AS and HM and  are the basis for neuroprotection in vivo.

Thus, present research activities aim at providing evidence of the capacity of phytochemically characterized extracts and flavonoid fraction of AS and HM to revert brain experimental ischemic lesions in vivo. To advance in the comprehension of the mechanisms involved, the oxidized/reduced glutathione ratio is currently assessed, as an indicator of the importance of redox equilibrium for cell survival. The blockade of the DNA breakage of neurons is also studied to understand the mechanisms through which active plant fractions might interfere cell death process. 

Papers in peer reviewed journals period 1999-2003

1. Dajas-Bailador F., Asencio M., Bonilla C., Scorza C., Etcheverry C., Reyes-Parada M., Silveira R., Protais P.,Russel G., Cassels B., Dajas F.
Dopaminergic pharmacology and antioxidant properties of pukateine, a natural product lead for the design of agents increasing dopamine neurotransmission.
General Pharmacology 32: 373 – 379, 1999.

2.- Evidences for a non-cholinergic function of acetylcholinesterase during development of chicken retina as hown by fasciculin.
Blasina MF, Faria AC, Gardino PF, Hokoc JN, Almeida OMMS, Mello FG, Arrut C., Dajas F.
Cell and Tissue Res 299:173-184, 2000.

3.- Do structural deviations between toxins adopting the same fold reflect functional differences ?
Ricciardi A, le Du MH, Khayati M, Dajas F, Boulain JC, Menez A, Ducancel F.
Jr. Biol. Chem 275:18302-18310, 2000

4.- Nicotine prevents striatal dopamine loss produced by 6-hydroxydopamine lesion in the substantia nigra.
Costa G, Abin JA, Dajas F.
Brain Res 888:336-342, 2001

5.- Intracerebral administration of 2,4-Dichloro-phenoxyacetic acid induces behavioral and neurochemical alterations in the rat brain.
Bertolozzi A, Evangelista de Duffard AM, Dajas F., Duffard R.,Silveira R.
Neurotoxicology 22:221-232, 2001

6.- Presynaptic involvement in the nicotine prevention of the dopamine loss provoked by 6-OHDA administration in the substantia nigra
Abin Carriquiry JA, McGregor R, Costa G., Urbanavicius J, Dajas F.
Neurotoxicity Res. 4 , 133-139, 2002.

7.-Neuroprotection by cholinergic and antioxidant mechanisms in experimental parkinsonism
F. Dajas, G. Costa, A. Abin.
Functional Neurology 17, 37-44, 2002.

8.- Screening of antioxidant activity of three Indian medicinal plants, traditionally used for the management of neurodegenerative diseases.
B.Auddy , M.Ferreira , F.Blasina , L. Lafon, F.Arredondo , F.Dajas , P.C.Tripathi and B.Mukherjee .
Jr. of Ethnopharmacol. , 84, 131-138, 2003 .

9.- Neuroprotection by flavonoids
Dajas F, Rivera F, Blasina F, Arredondo F, Abin A, Costa G, Echeverry C, Lafon L, Heizen H, Ferreira M, Morquio A.
Braz J Med Biol Res 36 , 1613-1620, 2003.

10.- Cell Culture Protection and in vivo Neuroprotective Capacity of Flavonoids
Dajas Federico, Rivera Felicia, Blasina Fernanda, Arredondo Florencia, Echeverry Carolina, Lafon Laura, Morquio Andrea and Heinzen Horacio
Neurotoxicty Res 5, 377.384:2003.

11.- Cytoprotection by Achyrocline satureoides (Lam) D.C. and some of its main flavonoids against oxidative stress.
Arredondo F, Blasina F, Echeverry C, Morquio A, Ferrerira M, Abin JA, Lafon L, Dajas F.
Jr. Ethnopharmacol. (in press)

Papers in Uruguayan Journals

1.  Tests paraclínicos para el diagnóstico del déficit atencional.

Bailador P., Dajas F.

Revista de Psiquiatría del Uruguay, 62:23-30,2000

2.-  Alta tasa de suicidio en Uruguay, IV: La situación epidemiológica actual.

       Dajas Federico

      Revista Médica del Uruguay 17: 24.32, 2001

3.-  Producción de radicales hidroxilo en sangre de pacientes ancianos

      hipertensos.

      Dajas F., Martínez A., Ferrari A., Ferreira M., Zeppi M., Pintos A.

      Revista Médica del Uruguay (in press)